Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

K-Ras-Activated Cells Can Develop into Lung Tumors When Runx3-Mediated Tumor Suppressor Pathways Are Abrogated

  • Lee, You-Soub (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Lee, Ja-Yeol (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Song, Soo-Hyun (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Kim, Da-Mi (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Lee, Jung-Won (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Chi, Xin-Zi (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University) ;
  • Ito, Yoshiaki (Cancer Science Institute of Singapore, National University of Singapore) ;
  • Bae, Suk-Chul (Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University)
  • Received : 2020.09.08
  • Accepted : 2020.09.10
  • Published : 2020.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

K-RAS is frequently mutated in human lung adenocarcinomas (ADCs), and the p53 pathway plays a central role in cellular defense against oncogenic K-RAS mutation. However, in mouse lung cancer models, oncogenic K-Ras mutation alone can induce ADCs without p53 mutation, and loss of p53 does not have a significant impact on early K-Ras-induced lung tumorigenesis. These results raise the question of how K-Ras-activated cells evade oncogene surveillance mechanisms and develop into lung ADCs. RUNX3 plays a key role at the restriction (R)-point, which governs multiple tumor suppressor pathways including the p14ARF-p53 pathway. In this study, we found that K-Ras activation in a very limited number of cells, alone or in combination with p53 inactivation, failed to induce any pathologic lesions for up to 1 year. By contrast, when Runx3 was inactivated and K-Ras was activated by the same targeting method, lung ADCs and other tumors were rapidly induced. In a urethane-induced mouse lung tumor model that recapitulates the features of K-RAS-driven human lung tumors, Runx3 was inactivated in both adenomas (ADs) and ADCs, whereas K-Ras was activated only in ADCs. Together, these results demonstrate that the R-point-associated oncogene surveillance mechanism is abrogated by Runx3 inactivation in AD cells and these cells cannot defend against K-Ras activation, resulting in the transition from AD to ADC. Therefore, K-Ras-activated lung epithelial cells do not evade oncogene surveillance mechanisms; instead, they are selected if they occur in AD cells in which Runx3 has been inactivated.

Keywords

References

  1. Canon, J., Rex, K., Saiki, A.Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C.G., Koppada, N., et al. (2019). The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217-223. https://doi.org/10.1038/s41586-019-1694-1
  2. Chi, X.Z., Lee, J.W., Lee, Y.S., Park, I.Y., Ito, Y., and Bae, S.C. (2017). Runx3 plays a critical role in restriction-point and defense against cellular transformation. Oncogene 36, 6884-6894. https://doi.org/10.1038/onc.2017.290
  3. Drosten, M., Guerra, C., and Barbacid, M. (2018). Genetically engineered mouse models of K-Ras-driven lung and pancreatic tumors: validation of therapeutic targets. Cold Spring Harb. Perspect. Med. 8, a031542. https://doi.org/10.1101/cshperspect.a031542
  4. DuPage, M., Dooley, A.L., and Jacks, T. (2009). Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4, 1064-1072. https://doi.org/10.1038/nprot.2009.95
  5. Feldser, D.M., Kostova, K.K., Winslow, M.M., Taylor, S.E., Cashman, C., Whittaker, C.A., Sanchez-Rivera, F.J., Resnick, R., Bronson, R., Hemann, M.T., et al. (2010). Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572-575. https://doi.org/10.1038/nature09535
  6. Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., and Barbacid, M. (2003). Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111-120. https://doi.org/10.1016/S1535-6108(03)00191-0
  7. Janne, P.A., Gray, N., and Settleman, J. (2009). Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat. Rev. Drug Discov. 8, 709-723. https://doi.org/10.1038/nrd2871
  8. Junttila, M.R., Karnezis, A.N., Garcia, D., Madriles, F., Kortlever, R.M., Rostker, F., Brown Swigart, L., Pham, D.M., Seo, Y., Evan, G.I., et al. (2010). Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567-571. https://doi.org/10.1038/nature09526
  9. Kemp, R., Ireland, H., Clayton, E., Houghton, C., Howard, L., and Winton, D.J. (2004). Elimination of background recombination: somatic induction of Cre by combined transcriptional regulation and hormone binding affinity. Nucleic Acids Res. 32, e92. https://doi.org/10.1093/nar/gnh090
  10. Lee, J.W. and Bae, S.C. (2020). Role of RUNX family members in G1 restriction point regulation. Mol. Cells 43, 182-187. https://doi.org/10.14348/molcells.2019.0319
  11. Lee, J.W., Kim, D.M., Jang, J.W., Park, T.G., Song, S.H., Lee, Y.S., Chi, X.Z., Park, I.Y., Hyun, J.W., Ito, Y., et al. (2019a). RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restrictionpoint. Nat. Commun. 10, 1897. https://doi.org/10.1038/s41467-019-09810-w
  12. Lee, J.W., Park, T.G., and Bae, S.C. (2019b). Involvement of RUNX and BRD family members in restriction point. Mol. Cells 42, 836-839. https://doi.org/10.14348/molcells.2019.0256
  13. Lee, K.S., Lee, Y.S., Lee, J.M., Ito, K., Cinghu, S., Kim, J.H., Jang, J.W., Li, Y.H., Goh, Y.M., Chi, X.Z., et al. (2010). Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer. Oncogene 29, 3349-3361. https://doi.org/10.1038/onc.2010.79
  14. Lee, Y.S., Lee, J.W., Jang, J.W., Chi, X.Z., Kim, J.H., Li, Y.H., Kim, M.K., Kim, D.M., Choi, B.S., Kim, E.G., et al. (2013). Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell 24, 603-616. https://doi.org/10.1016/j.ccr.2013.10.003
  15. Muzumdar, M.D., Dorans, K.J., Chung, K.M., Robbins, R., Tammela, T., Gocheva, V., Li, C.M., and Jacks, T. (2016). Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685. https://doi.org/10.1038/ncomms12685
  16. Podsypanina, K., Politi, K., Beverly, L.J., and Varmus, H.E. (2008). Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras. Proc. Natl. Acad. Sci. U. S. A. 105, 5242-5247. https://doi.org/10.1073/pnas.0801197105
  17. Samarakkody, A.S., Shin, N.Y., and Cantor, A.B. (2020). Role of RUNX family transcription factors in DNA damage response. Mol. Cells 43, 99-106. https://doi.org/10.14348/molcells.2019.0304
  18. Seo, W. and Taniuchi, I. (2020). The roles of RUNX family proteins in development of immune cells. Mol. Cells 43, 107-113. https://doi.org/10.14348/molcells.2019.0291
  19. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D., and Lowe, S.W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602. https://doi.org/10.1016/S0092-8674(00)81902-9
  20. Shao, D.D., Xue, W., Krall, E.B., Bhutkar, A., Piccioni, F., Wang, X., Schinzel, A.C., Sood, S., Rosenbluh, J., Kim, J.W., et al. (2014). KRAS and YAP1 converge to regulate EMT and tumor survival. Cell 158, 171-184. https://doi.org/10.1016/j.cell.2014.06.004
  21. Subramanian, J. and Govindan, R. (2008). Molecular genetics of lung cancer in people who have never smoked. Lancet Oncol. 9, 676-682. https://doi.org/10.1016/S1470-2045(08)70174-8
  22. Tuveson, D.A., Shaw, A.T., Willis, N.A., Silver, D.P., Jackson, E.L., Chang, S., Mercer, K.L., Grochow, R., Hock, H., Crowley, D., et al. (2004). Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375-387. https://doi.org/10.1016/S1535-6108(04)00085-6
  23. Weinberg, R.A. (2014). pRb and control of the cell cycle clock. In The Biology of Cancer, R.A. Weinberg, eds. (New York: Garland Science), pp. 275-329.
  24. Westcott, P.M., Halliwill, K.D., To, M.D., Rashid, M., Rust, A.G., Keane, T.M., Delrosario, R., Jen, K.Y., Gurley, K.E., Kemp, C.J., et al. (2015). The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. Nature 517, 489-492. https://doi.org/10.1038/nature13898
  25. Wistuba, I.I. and Gazdar, A.F. (2006). Lung cancer preneoplasia. Annu. Rev. Pathol. 1, 331-348. https://doi.org/10.1146/annurev.pathol.1.110304.100103
  26. Xue, J.Y., Zhao, Y., Aronowitz, J., Mai, T.T., Vides, A., Qeriqi, B., Kim, D., Li, C., de Stanchina, E., Mazutis, L., et al. (2020). Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature 577, 421-425. https://doi.org/10.1038/s41586-019-1884-x